The primary aim of this study is to determine the energy intake-independent effects of leptin on energy metabolism in lipodystrophic subjects. The major aspects of energy metabolism to be studied are: 1. Lipid metabolism, including fasting lipids, lipolysis and fatty acid turnover, and ectopic lipid storage. 2. Glucose metabolism, including fasting glucose, endogenous glucose production, and insulin sensitivity 3. Energy expenditure, including total and resting energy expenditure, skeletal muscle work efficiency, and spontaneous physical activity In addition, the effects of leptin on endocrine and autonomic function will be examined, including effects on the thyroid, gonadal, and adrenal axes, as well as blood pressure, body temperature, and heart rate. During the past fiscal year, this study continued active recruitment, and nearly completed enrollment. This study has involved introducing several new or specialized human physiologic research techniques at the NIH Clinical Center, including hyperinsulinemic euglycemic clamps to measure insulin sensitivity, use of stable isotope tracer techniques to measure endogenous glucose and lipid turnover, magnetic resonance spectroscopy to measure liver and intramyocellular triglyceride, measurement of energy expenditure using indirect calorimetry, and pulse analysis of secretion of luteinizing hormone. Based on the data obtained thus far, we have presented data supporting the idea that leptin improves insulin sensitivity independent of food intake, and we have published data showing that leptin increases gonadotropin pulsatility and sex steroids independent of food intake.